Liver Fibrosis Stage Research Articles

Relationship between fibrosis-4 index and new onset hypertension in the general population

Abstract Background/Introduction Non-alcoholic fatty liver disease (NAFLD) is a risk for cardiovascular events and malignant tumors as well as liver cirrhosis, and the risk increases with increasing fibrosis of the liver. Thus, the fibrosis-4 (FIB-4) index, developed as a noninvasive test to stage liver fibrosis, may predict the development of hypertension. Purpose The present study investigated the relationship of FIB-4 index with the prevalence and future development of hypertension in the general population. Methods A total of 16125 participants who visited our hospital for a physical check-up at least twice from 2008 to 2018 (male=9700, 52.0±12.3 year-old) were subjected for cross-sectional analysis. Among them, 3995 participants were hypertensive. The remaining 12111 normotensive participants (male=6984, 49.5±11.9 year-old) were followed up for the median of 1643 days with the endpoint being the development of hypertension, defined as systolic blood pressure ≥140mmHg, diastolic blood pressure ≥90mmHg or the use of antihypertensive medication. FIB-4 index was calculated as follows; (age×AST)/(platelet number×√ALT). Results Cross-sectional analysis revealed that FIB-4 index was higher in hypertensive than normotensive participants (1.40±0.74 vs. 1.09±0.54, p<0.001). During the follow-up, 2819 participants (45.7 per 1000 person-year) developed hypertension. The incidence was more frequent in male (55.6 per 1000 person-year) than female participants (32.7 per 1000 person-year, p<0.001). High level of FIB-4 index (≥2.67, n=194) showed a significant impact on the incident hypertension (80.5 per 1000 person-year) as compare with middle (≥1.30, <2.67, n=3082) or low level (<1.30, n=8835) of FIB-4 index (65.4 and 38.8 per 1000 person-year, respectively). Non-adjusted hazard ratio (HR) (95% confidence interval [CI]) of FIB-4 index for the new onset of hypertension was 1.483 (1.416-1.553). In multivariate Cox hazard analysis adjusted for sex, body mass index, systolic blood pressure, pulse rate, serum creatinine, uric acid, HbA1c, LDL-cholesterol, triglyceride, hemoglobin, current smoking, frequent alcohol consumption and family history of hypertension, FIB-4 index was an independent predictor of the development of hypertension (HR 1.321, 95%CI [1.213-1.438]). Similar results were obtained in analyses of male (HR 1.382, 95%CI [1.300-1.470]) and female subgroups (HR 1.369, 95%CI [1.230-1.524]). History of viral hepatitis or frequent alcohol consumption did not affect the results (data not shown). Conclusions FIB-4 index is a useful predictor of the development of hypertension in the general population. Increased risk of cardiovascular events in patients with NAFLD may partially be attributable to the development of or coexistence with hypertension.

Diagnostic role of the fibrosis-4 index and nonalcoholic fatty liver disease fibrosis score as a noninvasive tool for liver fibrosis scoring.

Nonalcoholic fatty liver disease (NAFLD) is characterized by liver fibrosis, which serves as a crucial indicator of its progression and prognosis. Owing to the limitations of biopsy, which is the gold standard for measuring liver fibrosis, a reliable and noninvasive marker is required. We evaluated the diagnostic role of the fibrosis-4 (FIB-4) index and nonalcoholic fatty liver disease fibrosis score (NFS) in patients with NAFLD with varying severities of liver fibrosis. The FIB-4 index and NFS were calculated using laboratory data from 121 patients who underwent liver biopsies between January 2022 and December 2023. The results were compared with those of the Scheuer scoring system for liver biopsies (F0, F1 + F2, and F3 + F4) to determine the sensitivity and specificity of the FIB-4 index and the liver disease fibrosis score in detecting and staging liver fibrosis. Twenty-one patients had advanced fibrosis (F3-F4), and 100 had minimal or mild fibrosis (F0-F2). The degree of liver fibrosis increased with decreased albumin, alanine aminotransferase and platelet count levels, and increasing age. Receiver operating characteristic curve analysis for the FIB-4 index and NFS revealed that the areas under the curve for the FIB-4 index and NFS were 0.895 (95% confidence interval: 0.836-0.954) and 0.882 (95% confidence interval: 0.813-0.952), respectively. The FIB-4 indices showed 95.24% sensitivity at a cutoff point of 1.30, and 85% specificity at a cutoff point of 2.67, while the NFS indices showed 95.24% sensitivity at -1.455 cutoff point and 95% specificity at a cutoff point of 0.676. The FIB-4 index and NFS may replace biopsy for the detection of fibrosis in patients with NAFLD.

Hepatic Bone Morphogenetic Protein and Activin Membrane-Bound Inhibitor Levels Decline in Hepatitis C but Are Not Associated with Progression of Hepatocellular Carcinoma.

Bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) is an antagonist of transforming growth factor (TGF)-β type 1 signaling. BAMBI functions as an anti-fibrotic protein and exerts pro- as well as anti-cancerogenic activities. Our study aimed to correlate hepatocyte BAMBI protein levels in hepatocellular carcinoma (HCC) with T stage, lymph node invasion, vessel invasion, grading, tumor size and Union for International Cancer Control (UICC) stage, as well as with liver inflammation and fibrosis stages. Hepatocyte BAMBI protein expression was assessed by immunohistochemistry in HCC tissues of 320 patients and non-tumor tissues of 51 patients. In the HCC tissues of the whole cohort and sex-specific analysis, BAMBI protein was not related to T stage, vessel invasion, lymph node invasion, histologic grade, UICC stage and tumor size. Accordingly, BAMBI was not associated with overall survival, recurrence-free and metastasis-free survival. BAMBI protein levels in tumor and non-tumor tissues were not related to inflammation and fibrosis grade. BAMBI protein levels in HCC tissues and non-tumor tissues from HCC patients, which were analyzed by immunoblot in a small cohort and by immunohistochemistry in the tissues of patients described above, were similar. Notably, BAMBI protein was low-abundant in HCC tissues of hepatitis C virus (HCV) compared to hepatitis B virus (HBV)-infected patients with comparable disease severity. Immunoblot analysis revealed reduced BAMBI protein in non-tumor tissues of patients with HCV in comparison to patients with HBV and normal human liver tissues. In summary, this analysis showed that hepatocyte BAMBI protein levels of patients with HCC are related to HCV infection rather than the severity of the underlying liver disease and cancer staging.

A multi-institutional study on Ultrasound image analysis for staging HBV-derived liver fibrosis: a potential non-invasive alternative to liver stiffness measurement

Background: Liver stiffness measurement is principal for staging liver fibrosis but not included in routine examinations. We investigated whether comparable diagnostic performance can be achieved by mining ultrasound images and developing a novel serum index (NSI). Methods: Texture features were extracted from ultrasound images. Spearman correlation and logistics regression selected independent variables for significant (F≥2) and advanced (F≥3) fibrosis. We compared the diagnostic performance of transient elastography (TE), ultrasound image biomarker (UIB), conventional serum indices (APRI, FIB-4, GPR), and NSI in 365 chronic hepatitis B patients. Results: Among patients, 52.1% had significant fibrosis and 24.2% had advanced fibrosis. PLT, GGT, prealbumin, and globulin were incorporated into NSI. In the validation group, TE achieved the best performance (AUC: 0.765 [0.690-0.849] for significant fibrosis; 0.812 [0.745-0.878] for advanced fibrosis), followed by UIB (AUC: 0.712 [0.629-0.795]; 0.678 [0.595-0.763]) and NSI (AUC: 0.630 [0.534-0.725]; 0.659 [0.572-0.745]), outperforming conventional indices. Conclusions: Texture analysis enhances ultrasound's diagnostic utility, but TE remains superior. When TE is unavailable, ultrasound image analysis and NSI, incorporating prealbumin, can serve as alternative tools for fibrosis staging.

Recent advances of nanomaterials in imaging liver fibrosis

AbstractLiver fibrosis is a pathological process resulting from prolonged exposure to various injury factors. It is characterized by the abnormal proliferation and activation of hepatic stellate cells and excessive deposition of extracellular matrix. If left untreated, it can progress to cirrhosis, liver failure, and even liver cancer. There is currently no efficient and accurate clinical diagnostic method for early liver fibrosis. Therefore, there is an urgent need to address the challenge of accurate staging and early diagnosis of liver fibrosis in clinical practice. Recently, nanomaterials have demonstrated significant potential for enhancing the diagnosis of liver fibrosis. Nanomaterials possess the ability to precisely identify and target the microenvironment associated with liver fibrosis. By enhancing their enrichment in the target area, nanomaterials can improve imaging contrast of fibrosis lesions in the liver, thereby enabling accurate diagnosis of liver fibrosis. Accordingly, this review delves into the latest research and advancements concerning nanomaterials in liver fibrosis diagnosis.

Comparison of Two-Dimensional Shear Wave Elastography Between Two Different Instruments for Hepatocellular Carcinoma Patients.

This study aimed to investigate and compare 2-dimensional shear wave elastography (2D-SWE) measurements and influencing factors among 2 different devices and to evaluate the ability and influencing factors of these measurements to assess liver fibrosis. From October 2022 to September 2023, 290 hepatocellular carcinoma (HCC) patients and 30 healthy volunteers were prospectively included. The 2D-SWE measurements were performed using AixPlorer V (SEmean) and APLIO i900 (CEmean). This study compared 2D-SWE measurements between instruments for evaluating the liver fibrosis stage and analyzed the potential influencing factors. The 2D-SWE measurements obtained by the 2 instruments were significantly different (P < .001), but the differences were significant only for patients with stage F4 liver fibrosis (P < .001) and not for volunteers or patients with stage F0-F3 liver fibrosis (all P > .050). Multivariate linear regression analysis revealed that the factors independently influencing the SEmean were alanine aminotransferase (ALT) (P = .034) and liver fibrosis stage (P < .001), while fibrosis stage (P = .028) was the only factor influencing the CEmean. Although 2D-SWE from the 2 different instruments was capable of detecting liver fibrosis, it yielded varying results in HCC patients. These discrepancies were predominantly observed in patients with F4 liver fibrosis but not in healthy adults or patients with F0-F3 liver fibrosis. One potential contributing factor to the differences between instruments could be ALT levels.

Cellular fibronectin-targeted fluorescent aptamer probes for early detection and staging of liver fibrosis

Liver fibrosis is a key process in the progression of chronic liver disease to cirrhosis. Currently, early diagnosis and precise staging of liver fibrosis remain great challenges. Extracellular matrix (ECM) molecules expressed specifically during liver fibrosis are ideal targets for bioimaging and detection of liver fibrosis. Here, we report that fluorescent probes based on a nucleic acid aptamer (ZY-1) targeting cellular fibronectin (cFN), a critical ECM molecule significantly accumulating during liver fibrosis, are promising bioimaging agents for the staging of liver fibrosis. In the work, the outstanding binding affinity of ZY-1 to cFN was validated through an in vitro model of human-derived hepatic stellate cells (HSCs). Subsequently, we constructed different ZY-1-based fluorescent probes and explored the real-time imaging performance of these fluorescent probes in CCl4-induced mouse models of different liver fibrosis stages. The ZY-1-based fluorescent probes, for the first time, effectively identified and distinguished early-stage liver fibrosis (stage 3 of Ishak 6) from advanced liver fibrosis (stage 5 of Ishak 6). The proof-of-concept study provides compelling evidences that ZY-1-based probes are a promising tool for the early diagnosis and staging of liver fibrosis and paves the way for further development of clinical-related diagnosis strategies for fibrotic diseases of the liver and other organs. Statement of significanceCurrently, early diagnosis and accurate staging of liver fibrosis continue to present significant challenges. This study demonstrates that fluorescent probes based on the nucleic acid aptamer ZY-1, which targets cellular fibronectin (cFN)—a crucial extracellular matrix (ECM) molecule that significantly accumulates during liver fibrosis—are promising bioimaging agents for staging liver fibrosis. The ZY-1-based fluorescent probes effectively identified and differentiated early-stage liver fibrosis from advanced liver fibrosis. This proof-of-concept study not only provides compelling evidence that ZY-1-based probes show promise for the early diagnosis and staging of liver fibrosis but also paves the way for further investigations into the use of ZY-1 in detecting other diseases associated with cFN.

A longitudinal 5-year study for the prediction of HCC, death and liver decompensation by ARFI elastography.

Numerous studies have evaluated elastography for the staging of liver fibrosis. Fewer studies were performed investigating the prognostic relevance using transient elastography (TE), although with promising results. This study was designed to evaluate the prognostic relevance of ARFI elastography. Patients receiving ARFI elastography in our ultrasound department between 2010 and 2012 were initially screened for an ARFI examination with a clinical follow-up of at least 5 years. The following events were recorded: liver related death, liver unrelated death, HCC, liver decompensation/ variceal bleeding. A total of 335 patients were included in the final analysis with an ARFI examination of the liver and a follow-up of 60 months. Within the observation interval the number of events with corresponding AUROCs (shown with 95% confidence interval) were: overall death (n=49, 0.76 [0.69 - 0.83]), liver related death (n=25, 0.85 [0.77 - 0.93]), liver unrelated death (n=24, 0.66 [0.55 - 0.77]), HCC (n=15, 0.80 [0.72 - 0.87]), liver related complications/variceal bleeding (n=34, 0.87 [0.82 - 0.93]). In the group of patients with ARFI values suggestive of cirrhosis (equal to or above 1.80 m/s; n=110) higher values (<2.5 m/s vs. >= 2.5 m/s) where associated with a significant decline in liver related survival (p=0.007). ARFI elastography seems to have a good diagnostic accuracy for the prediction of liver related death and decompensation. Further it seems to allow a risk stratification in patients with cirrhosis suspicious elastography values.

GLCV-NET: An automatic diagnosis system for advanced liver fibrosis using global–local cross view in B-mode ultrasound images

Background and objective: Advanced liver fibrosis is a critical stage in the evaluation of chronic liver disease (CLD), holding clinical significance in the development of treatment strategies and estimating the disease progression. Methods:This paper proposes an innovative Global–Local Cross-View Network (GLCV-Net) for the automatic diagnosis of advanced liver fibrosis from ultrasound (US) B-mode images. The proposed method consists of three main components: 1. A Segmentation-enhanced Global Hybrid Feature Extractor for segmenting the liver parenchyma and extracting global features; 2. A Heatmap-weighted Local Feature Extractor for selecting candidate regions and automatically identifying suspicious areas to construct local features; 3. A Scale-adaptive Fusion Module to balance the contributions of global and local scales in evaluating advanced liver fibrosis. Results:The predictive performance of the model was validated on an internal dataset of 1003 chronic liver disease (CLD) patients and an external dataset of 46 CLD patients, both subjected to liver fibrosis staging through pathological assessment. On the internal dataset, GLCV-Net achieved 86.9% accuracy, 85.0% recall, 85.4% precision, and 85.2% F1-score. Further validation on the external dataset confirmed its robustness, with scores of 86.1% in accuracy, 83.1% in recall, 80.8% in precision, and 81.9% in F1-score. Conclusion:These results underscore the GLCV-Net’s potential as a promising approach for non-invasively and accurately diagnosing advanced liver fibrosis in CLD patients, breaking through the limitations of traditional methods by integrating global and local information of liver fibrosis, significantly enhancing diagnostic accuracy.

AHCCⓇ inhibited Hepatic Stellate Cells Activation by Regulation of Cytoglobin induction via TLR2-SAPK/JNK pathway and Collagen Production via TLR4-NFκB pathway.

[Introduction] Cirrhosis, which represents the end stage of liver fibrosis, remains a life-threatening condition without effective treatment. Therefore, prevention of the progression of liver fibrosis through lifestyle habits such as diet and exercise is crucial. The functional food AHCCⓇ has been reported to be effective in improving the pathophysiology of various liver diseases. In this study, the aim was to analyze the influence of AHCCⓇ on hepatic stellate cells, which are responsible for liver fibrosis. [Materials and Methods] Eight-week-old male C57BL6/j mice were induced liver fibrosis by intraperitoneal injection of carbon tetrachloride. Simultaneously, they were orally administered 3% AHCCⓇto investigate its impact on the progression of liver fibrosis. Using the human hepatic stellate cell line HHSteC, we analyzed the influence of AHCCⓇ on the expression of molecules related to hepatic stellate cell activation. [Results] The administration of AHCCⓇ resulted in reduced expression of collagen1a, alpha smooth muscle actin (αSMA), and Heat shock protein 47 in the liver. Furthermore, the expression of cytoglobin, a marker for quiescent hepatic stellate cells, was enhanced. In vitro study, it was confirmed that AHCCⓇ inhibited αSMA by induction of cytoglobin via upregulating the SAPK/JNK pathway through toll-like receptor (TLR) 2. In addition, AHCCⓇ suppressed collagen1a production by hepatic stellate cells through TLR4-NFκβ pathway. [Conclusion] AHCCⓇ was suggested to suppress hepatic fibrosis by inhibition of hepatic stellate cells activation. Daily intake of AHCCⓇ from mild fibrotic stages may have the potential to prevent the progression of liver fibrosis.

Lipid and carbohydrate metabolism disturbances in children with chronic hepatitis C

Aim. To study the state of lipid and carbohydrate metabolism, body composition, liver parenchyma structure in children with chronic hepatitis C (CHC).Materials and methods. 63 children with CHC examined at DNACIB in 2022–2023 (anthropometry, laboratory examination, bioimpedance analysis (BIA) of body composition, liver elastography with evaluation of steatosis).Results. Abnormalities of lipid metabolism were detected in 1/3 of children with CHC even with normal and low body mass index (BMI). Signs of insulin resistance (HOMAIR&gt;3,2) were found in 54% of children with CHC. One third of patients with insulin resistance have liver steatosis, which significantly exceeds the frequency of steatosis registration among children without insulin resistance. There was a tendency for the frequency of insulin resistance to increase in proportion to the progression of the stage of liver fibrosis. No association between hepatitis virus genotype and disorders of lipid and carbohydrate metabolism was found.Conclusion. As a result of hepatitis C virus exposure in children with CHC, the risk of insulin resistance formation increases, which may be one of the pathogenetic mechanisms of liver steatosis development, increasing the risk of severe liver fibrosis formation and unfavorable outcome of the disease.

Intestinal microbiota and metabolically associated steatotic liver disease: current understanding of the problem. Review

Cross‑interaction of microbes, microbial products, and the intestinal barrier are components of the so‑called «intestine‑liver axis», as the liver and intestines have a close two‑way relationship. In patients with metabolically associated steatotic liver disease (MASLD), significant characteristic changes in the intestinal microbiome are observed, in particular, the growth of gram‑negative bacteria, which contributes to the formation of a pro‑inflammatory status (primarily due to endotocins) and disruption of metabolic processes, while an increase in Bacteroides and Ruminococcus and a decrease in Prevotella are associated with severe stages of liver fibrosis. Intestinal microbiota modulates the pool of bile acids thereby affecting metabolic homeostasis and pro‑inflammatory processes. Dysbiosis associated with MASLD is characterized by an excess of bacteria — producers of secondary bile acids, which are one of the factors in the progression of metabolically associated steatohepatitis. In addition, dysbiosis leads to increased production of short‑chain fatty acids, which promotes gluconeogenesis, synthesis and accumulation of toxic lipids in the liver and, accordingly, the development and progression of MASLD. But liver function disorders connected with dysbiosis are associated not only with intestinal bacteria, but also with fungi and viruses. According to the results of recent studies, MASLD is associated with a significant diversity of the mycobiome and has certain differences in the progression of the disease depending on the degree of liver inflammation and the stage of fibrosis. Chronic hyperproduction of endogenous ethanol (Klebsiella pneumoniae, Escherichia, Candida, etc.) is an important factor in the pathogenesis of MASLD, as it disrupts glucose and lipid metabolism, contributing to the formation of liver steatosis and steatohepatitis. Ultrastructural and functional changes of mitochondria are recognized determinants in the pathogenesis of MASLD. Mitochondria and intestinal microbiota have a bidirectional relationship: microbiota supplies metabolites for mitochondrial metabolism and redox homeostasis, and the development of dysbiosis contributes to oxidative stress and proinflammatory status — key factors in the development of metabolically associated steatohepatitis. Mitochondria can also modulate intestinal microflora by affecting the permeability of the intestinal barrier. The data presented in the article expand our knowledge about the interaction of the liver and the intestine and inspire the development of new promising therapeutic approaches to the treatment of MASLD, which involve a synergistic effect on the intestinal microbiota, microbiome, virome, and mitochondrial function.

Impairment of health-related quality of life among people with type 2 diabetes and advanced liver fibrosis

People with type 2 diabetes mellitus (T2DM) show a high prevalence of steatotic liver disease (SLD), and especially metabolic dysfunction-associated steatotic liver disease (MASLD), with liver fibrosis. Their health-related quality of life (HRQL) is affected by multiple in part overlapping factors and aggravated by metabolic and liver-related comorbidities, including liver fibrosis stage. The aim of this study was to investigate the effect size of advanced fibrosis (AF) on the HRQL in people with T2DM. A total of 149 individuals with T2DM treated at a primary care provider within the German disease management program (DMP) were included in the final analysis. Vibration-controlled transient elastography (VCTE) was used to non-invasively detect steatosis and AF. The EQ-5D-3L questionnaire was used to assess the HRQL. Uni- and multivariable linear regression models were used to identify independent predictors of impaired HRQL. The majority was male (63.1%), and the median age was 67 years (IQR 59; 71). In the entire cohort, the prevalence of MASLD and AF was 70.7% and 19.5%, respectively. People with T2DM and AF had an overall lower HRQL in comparison to those without AF (p < 0.001). Obesity (β: − 0.247; 95% CI − 0.419, − 0.077) and AF (β: − 0.222; 95% CI − 0.383, − 0.051) remained independent predictors of a poor HRQL. In turn, T2DM-related comorbidities were not predictive of an impaired HRQL. Obesity and AF negatively affect the HRQL in patients with SLD and T2DM in primary care. Awareness of liver health and specific interventions may improve patient-reported and liver-related outcomes in people with T2DM.

Associations between cuprotosis-related genes and the spectrum of metabolic dysfunction-associated fatty liver disease: An exploratory study.

To explore the associations between cuprotosis-related genes (CRGs) across different stages of liver disease in metabolic dysfunction-associated fatty liver disease (MAFLD), including hepatocellular carcinoma (HCC). We analysed several bulk RNA sequencing datasets from patients with MAFLD (n = 331) and MAFLD-related HCC (n = 271) and two MAFLD single-cell RNA sequencing datasets. To investigate the associations between CRGs and MAFLD, we performed differential correlation, logistic regression and functional enrichment analyses. We also validated the findings in an independent Wenzhou PERSONS cohort of MAFLD patients (n = 656) used for a genome-wide association study (GWAS). GLS, GCSH and ATP7B genes showed significant differences across the MAFLD spectrum and were significantly associated with liver fibrosis stages. GLS was closely associated with fibrosis stages in patients with MAFLD and those with MAFLD-related HCC. GLS is predominantly expressed in monocytes and T cells in MAFLD. During the progression of metabolic dysfunction-associated fatty liver to metabolic-associated steatohepatitis, GLS expression in T cells decreased. GWAS revealed that multiple single nucleotide polymorphisms in GLS were associated with clinical indicators of MAFLD. GLS may contribute to liver inflammation and fibrosis in MAFLD mainly through cuprotosis and T-cell activation, promoting the progression of MAFLD to HCC. These findings suggest that cuprotosis may play a role in MAFLD progression, potentially providing new insights into MAFLD pathogenesis.

The relationship between diabetes mellitus and non-alcoholic fatty liver disease: a clinical and instrumental paired study

To study the impact of type 2 diabetes mellitus (DM2) on the severity of liver steatosis and fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). To conduct a paired case-control study 2989 patients were examined at the Federal Research Center of Nutrition, Biotechnology and Food Safety. Pairs were matched by gender and age and distributed into groups: NAFLD + DM2+ (n=313), NAFLD + DM2- (n=313) and a control group of patients without NAFLD and without DM2 (n=313). The severity of liver steatosis was determined by measuring the controlled attenuation parameter. The severity of liver fibrosis was determined by measuring the liver stiffness measurement. Body composition of the patients was determined using bioimpedance measurements. Indicators of lipid and carbohydrate metabolism, and the serum activity of liver enzymes was determined by standard biochemical methods. In NAFLD + DM2+ group compared to NAFLD + DM2- group, and in NAFLDM + DM2-compared to the control group, weight, BMI, waist and hip circumference, waist-to-hip ratio were higher, while in all. In NAFLD + DM2+ and NAFLD + DM2- groups the volume of fat mass directly correlated with the level of blood triglycerides (r=0.21), HbA1с (r=0.32) and fasting blood glucose (r=0.35), and inversely correlated with high-density lipoproteins (r=-0.19). In NAFLD + DM2+ group versus NAFLD + DM2- group severe steatosis (S3, 78% versus 59.4%; p<0.001) and severe fibrosis (F4, 8% vs 2.6%; p<0.001) was more common; 70% of patients in the NAFLD + DM2- group had no liver fibrosis according to elastography (F0), while in the NAFLD + DM2+ group only 43.2% of patients had no liver fibrosis (p<0.0001). When NAFLD is accompanied by DM2, there is an increase in total fat mass, the severity of steatosis and liver fibrosis, and an associated deterioration of lipid metabolism. More than half of these patients have various stages of liver fibrosis, which indicates the progressive nature of the disease.

Liver fibrosis is closely linked with metabolic-associated diseases in patients with autoimmune hepatitis.

This cross-sectional study aimed to investigate the impact of metabolic-associated diseases (MADs) on patients with autoimmune hepatitis (AIH). The study analyzed the clinical characteristics of 283 AIH patients who underwent liver biopsy between January 2016 and February 2022 in Ruijin Hospital, Shanghai, China. Among the identified AIH patients (n = 283), 87.3%, 23.0%, or 43.1% had MADs, non-alcoholic fatty liver disease (NAFLD), or severe fibrosis, respectively. The proportion of diabetes mellitus (DM) was significantly higher in patients with severe liver fibrosis than in those with mild or moderate fibrosis in the AIH cohort (31.1% vs. 18.0%, p < 0.05). Fibrosis was also more severe in patients with NAFLD than in those without (53.8% vs. 39.9%, p < 0.05). Age, Plts, IgG and the presence with MADs were identified as independent predictors of the severity of inflammation in AIH patients. Moreover, severe liver fibrosis (stages 3 to 4) was independently associated with male (OR, 2.855; p = 0.025), γ-GT (OR, 0.997; p = 0.007), and combination with MADs (OR, 4.917; p = 0.006). Furthermore, combination with DM was also an independent predictor of severe liver fibrosis in AIH patients (OR, 2.445, p = 0.038). Concurrent MADs, common in AIH patients, is an independent risk factor for severe fibrosis or inflammation; of note, combination with DM was also an independent predictor of severe liver fibrosis in AIH patients. While managing with AIH, routine assessment of co-existing MADs, especially DM, is also important.

Redox Homeostasis and Non-Invasive Assessment of Significant Liver Fibrosis by Shear Wave Elastography.

Hepatic fibrosis with various origins can be estimated non-invasively by using certain biomarkers and imaging-based measurements. The aim of our study was to examine redox homeostasis biomarkers and liver stiffness measurements for the assessment of significant liver fibrosis in different etiologies of chronic liver diseases. A cohort study consisting of 88 chronic liver disease patients of both sexes (age 49.1 ± 14.7 years) was performed. Cytokine profiles as well as redox homeostasis characteristics were determined. Liver fibrosis stages were assessed with shear wave elastography. The plasma levels of four cytokines showed no significant alteration between the four fibrotic stages; however, higher values were measured in the F2-4 stages. Free sulfhydryl group concentration, the marker of redox homeostasis, was lower in significant fibrosis (F0-F1: 0.36 ± 0.06 vs. F2-4: 0.29 ± 0.08 mmol/L, p < 0.05). Higher chemiluminescence values, as free radical-antioxidant parameters, were detected in advanced fibrosis stages in erythrocytes (F0-F1: 36.00 ± 37.13 vs. F2-4: 51.47 ± 44.34 RLU%). These data suggest that oxidative stress markers can predict significant fibrosis, with the aim of reducing the number of protocol liver biopsies in patients unlikely to have significant disease; however, their role in distinguishing between the certain fibrosis groups needs further studies.

Development and validation of a nomogram for predicting advanced liver fibrosis in patients with chronic hepatitis B.

The progression of chronic hepatitis B (CHB) to liver fibrosis and even cirrhosis is often unknown to patients, but noninvasive markers capable of effectively identifying advanced liver fibrosis remains absent. Based on the results of liver biopsy, we aimed to construct a new nomogram to validate the stage of liver fibrosis in CHB patients by the basic information of CHB patients and routine laboratory tests. Patients with CHB diagnosed for the first time in the First Affiliated Hospital of Anhui Medical University from 2010 to 2018 were selected, and their basic information, laboratory tests and liver biopsy information were collected. Eventually, 974 patients were enrolled in the study, while all patients were randomized into a training cohort (n = 732) and an internal validation cohort (n = 242) according to a 3:1 ratio. In the training cohort, least absolute shrinkage and selection operator (Lasso) regression were used for predictor variable screening, and binary logistic regression analysis was used to build the diagnostic model, which was ultimately presented as a nomogram. The predictive accuracy of the nomograms was analyzed by running operating characteristic curve (ROC) to calculate area under curve (AUC), and the calibration was evaluated. Decision curve analysis (DCA) was used to determine patient benefit. In addition, we validated the built models with internal as well as external cohort (n = 771), respectively. Ultimately, the training cohort, the internal validation cohort, and the external validation cohort contained sample sizes of 188, 53, and 149, respectively, for advanced liver fibrosis. Gender, albumin (Alb), globulin (Glb), platelets (PLT), alkaline phosphatase (AKP), glutamyl transpeptidase (GGT), and prothrombin time (PT) were screened as independent predictors. Compared with the aminotransferase-to-platelet ratio index (APRI), fibrosis-4 index (FIB-4), and King's score, the model in the training cohort (AUC = 0.834, 95% CI 0.800-0.868, p < 0.05) and internal validation cohort (AUC = 0.804, 95% CI 0.742-0.866, p < 0.05) showed the best discrimination and the best predictive performance. In addition, DCA showed that the clinical benefit of the nomogram was superior to the APRI, FIB-4 and King's scores in all cohorts. This study constructed a validated nomogram model with predictors screened from clinical variables which could be easily used for the diagnosis of advanced liver fibrosis in CHB patients.

A combination model of CT-based radiomics and clinical biomarkers for staging liver fibrosis in the patients with chronic liver disease

A combined model was developed using contrast-enhanced CT-based radiomics features and clinical characteristics to predict liver fibrosis stages in patients with chronic liver disease (CLD). We retrospectively analyzed multiphase CT scans and biopsy-confirmed liver fibrosis. 160 CLD patients were randomly divided into 7:3 training/validation ratio. Clinical laboratory indicators associated with liver fibrosis were identified using Spearman's correlation and multivariate logistic regression correlation. Radiomic features were extracted after segmenting the entire liver from multiphase CT images. Feature dimensionality reduction was performed using RF-RFE, LASSO, and mRMR methods. Six radiomics-based models were developed in the training cohort of 112 patients. Internal validation was conducted on 48 randomly assigned patients. Receptor Operating Characteristic (ROC) curves and confusion matrices were constructed to evaluate model performance. The radiomics model exhibited robust performance, with AUC values of 0.810 to 1.000 for significant fibrosis, advanced fibrosis, and cirrhosis. The integrated clinical-radiomics model had superior diagnostic efficacy in the validation cohort, with AUC values of 0.836 to 0.997. Moreover, these models outperformed established biomarkers such as the aspartate aminotransferase to platelet ratio index (APRI) and the fibrosis 4 score (FIB-4), as well as the gamma glutamyl transpeptidase to platelet ratio (GPR), in predicting the fibrotic stages. The clinical-radiomics model holds considerable promise as a non-invasive diagnostic tool for the assessment and staging of liver fibrosis in the patients with CLD, potentially leading to better patient management and outcomes.

Magnetic Resonance Elastography for Staging Liver Fibrosis in the Oncopig.

This pilot study investigated the feasibility of using magnetic resonance elastography (MRE) for the non-invasive detection and quantification of liver fibrosis in the Oncopig cancer model. Seven 8-week-old Oncopigs underwent alcoholic liver fibrosis induction and serial MRE imaging and liver biopsy at 1, 2, and 3 months post procedure. MRE was utilized to quantify liver stiffness, and liver fibrosis was histologically graded using the METAVIR system. The primary outcome measure was the capability to detect and quantify liver fibrosis using MRE with radiologic-pathologic correlation. Liver fibrosis induction, MRE imaging, and liver biopsy were successfully performed. MRE liver fibrosis was evident in 57% (4/7), 50% (3/6), and 40% (2/5) animal subjects 1, 2, and 3 months after fibrosis induction, with mean liver stiffness of 2.94, 3.25, and 2.91 kPa, respectively. Histological liver fibrosis was noted in 71% (5/7), 100% (5/5), and 100% (5/5) of animal subjects with available tissue samples. There was no significant statistical correlation between the MRE-measured liver stiffness and the METAVIR fibrosis scores. In conclusion, quantifiable liver fibrosis may be induced in the Oncopig. MRE has potential utility in non-invasively detecting liver stiffness in this large-animal preclinical model, though tissue biopsy was more sensitive in demonstrating disease.